Abstract
Enhancers are cis-regulatory DNA elements that positively regulate the transcription of target genes in a tissue-specific manner, and dysregulation of target genes could lead to various diseases, such as cancer. Recent studies have shown that enhancers can regulate microRNAs (miRNAs) and participate in their biological synthesis. However, the network of enhancer-regulated miRNAs across multiple cancers is still unclear. Here, a total of 2,418 proximal enhancer–miRNA interactions and 1,280 distal enhancer–miRNA interactions were identified through the integration of genomic distance, co-expression, and 3D genome data in 31 cancers. The results showed that both proximal and distal interactions exhibited a significant cancer type-specific feature trend at the tissue level rather than at the single-cell level, and there was a noteworthy positive correlation between the expression of the miRNA and the number of enhancers regulating the same miRNA in most cancers. Furthermore, we found that there was a high correlation between the formation of enhancer–miRNA pairs and the expression of enhancer RNAs (eRNAs) whether in distal or proximal regulation. The characteristics analysis showed that miRes (enhancers that regulated miRNAs) and non-miRes presented significant differences in sequence conservation, guanine–cytosine (GC) content, and histone modification signatures. Notably, GC content, H3K4me1, and H3K36me3 were present differently between distal and proximal regulation, suggesting that they might participate in chromosome looping of enhancer–miRNA interactions. Finally, we introduced a case study, enhancer: chr1:1186391–1186507 ∼ miR-200a was highly relevant to the survival of thyroid cancer patients and a cis-eQTL SNP on the enhancer affected the expression of the TNFRSF18 gene as a tumor suppressor.
Highlights
Enhancers are cis-regulatory DNA regulatory elements that positively regulate the transcription of target genes in a spatiotemporal-specific manner
To further explore the mechanism of enhancer–miRNA regulation in cancers, we identified a series of enhancer-regulated miRNAs in 33 cancer types
MiR-28 is regulated by two enhancers, and this interaction only appears in lung adenocarcinoma (LUAD) across all 31 cancer types
Summary
Enhancers are cis-regulatory DNA regulatory elements that positively regulate the transcription of target genes in a spatiotemporal-specific manner. Previous studies have shown that enhancer activity is affected by the Enhancer Regulated microRNAs in 31 Cancers enhancer RNA (eRNA), which is transcribed bidirectionally from active regulatory enhancers and plays a key role in regulating downstream gene expression. Other recent studies showed that enhancers (including typical enhancers and super enhancers) are found to regulate miRNA expression and participate in the biological synthesis of miRNAs regulated by Drosha/DGCR8 (Yun et al, 2018; Wood et al, 2019). These studies suggested that enhancers are involved in miRNA regulatory networks and contribute greatly to tumorigenesis and development
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